ABSTRACT Inherited serum deficiency disorders, such as hemophilia and ?1-antitrypsin (AAT) deficiency, have been considered ideal candidates for corrective gene therapy. In this regard, viral vector-mediated transduction of the liver has been proposed for a number of such disorders wherein hepatocytes represent the normal physiologic source of the deficient serum factor. Specifically, adeno-associated virus (AAV)-based vectors have demonstrated utility in hemophilia in animal models and this approach is presently being translated to the context of human clinical trials. Despite these findings, a number of considerations have led to the recognition that alternative vector approaches may be required. In the first instance, vector-related liver toxicities make consideration of non-hepatic sourcing of serum factors desirable. In addition, for some inherited deficiency disorders, such as AAT deficiency, AAV-mediated in vivo transduction of the liver has not achieved adequate levels of the deficient serum factor to achieve effective gene therapy. We propose here to test our highly original approach to accomplish genetic correction of a prototype serum deficiency disorders ? AAT deficiency lung disease. Our technology platform will clearly have broad field impact. In the first regard, we provide the technical basis for a new translational approaches for the full range of inherited serum deficiency disorders. In the second regard, we will engineer Ad as a vehicle capable of long term gene expression. This fundamental change in this important vector's functionalities will dramatically expand the range of utilities whereby it can be employed.